Autophagy Heterogeneity and Tumor Metastasis

自噬异质性与肿瘤转移

基本信息

批准号：
10212775
负责人：
HONG-GANG WANG
金额：
$ 41.7万
依托单位：
PENNSYLVANIA STATE UNIV HERSHEY MED CTR
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-04-01 至 2023-03-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10212775
关键词：
Affect Autophagocytosis Breast Cancer Cell Breast Cancer Model Breast cancer metastasis Cancer Cell Growth Cell Communication Cell Survival Cells Cessation of life Chloroquine Clinical Trials Collaborations Communication Complex Coupling Cytomegalovirus Degradation Pathway Dominant-Negative Mutation Fatty acid glycerol esters Fibronectins Gene Expression Profiling Goals Growth Heterogeneity Homeostasis Hydroxychloroquine Hypoxia Integrins Knowledge Label MDA MB 231 Maintenance Malignant - descriptor Malignant Neoplasms Mediating Metabolic Metastatic Neoplasm to the Lung Monitor Mus Neoplasm Circulating Cells Neoplasm Metastasis Nutrient Organelles Outcome Oxygen Phenotype Phosphotransferases Physiological Primary Neoplasm Prognosis Protein-Serine-Threonine Kinases Proteins Proteomics Recycling Response Elements Role Signal Transduction Stress System Testing Therapeutic Tumor Promoters Tumor Suppressor Proteins Xenograft procedure base cancer cell cancer survival cancer therapy chemotherapy epithelial to mesenchymal transition improved in vivo inhibitor/antagonist insight mammary mechanotransduction mitochondrial metabolism mouse model mutant neoplastic cell novel nutrient deprivation patient response promoter response targeted cancer therapy transcriptome tumor tumor growth tumor heterogeneity tumor hypoxia tumor microenvironment tumor progression vector

项目摘要

The goal of this project is to investigate the intratumoral heterogeneity of autophagy activity in breast cancer metastasis. Autophagy is a highly conserved lysosomal degradation pathway that is induced in response to environmental or intracellular stress for the recycling of damaged proteins or organelles and the maintenance of cellular homeostasis. While autophagy serves as a tumor suppressor to limit malignant transformation, it also enables the growth and survival of cancer cells within the nutrient- and oxygen-deprived tumor microenvironment (TME). Hypoxia is associated with enhanced metastasis and poor prognosis; however, the role of hypoxia- induced autophagy in tumor progression is not clear. We have established a novel orthotopic model of breast cancer in which autophagy is physiologically and reversibly suppressed in hypoxic tumor regions. Notably, the loss of autophagy in hypoxic tumor regions significantly increases lung metastasis without affecting primary tumor growth. Moreover, the loss of hypoxia-induced autophagy also enhances lung metastasis compared to tumors in which autophagy is constitutively suppressed. Collectively, we hypothesize that the loss of hypoxia- induced autophagy increases tumor stress to promote metastasis via collaboration with nearby autophagy- competent cells to establish tumor subpopulations with high and low autophagic activity that drive metastasis through the fibronectin-integrin signaling and metabolic coupling. The hypotheses will be tested in two Specific Aims: 1) To identify and characterize the tumor subpopulations with increased metastatic potential during the loss of hypoxia-induced autophagy or induction of autophagy heterogeneity; 2) To investigate the mechanisms by which heterogeneous autophagy activity mediates intra-tumor cell communication. Completion of these studies will significantly enhance our understanding of autophagy in tumor metastasis and provide insight into the appropriate modulation of autophagy for cancer therapy.

该项目的目的是研究乳腺癌自噬活动的肿瘤内异质性转移。自噬是一种高度保守的溶酶体降解途径，响应于环境或细胞内应力，用于回收受损的蛋白质或细胞器，并维护细胞稳态。虽然自噬是抑制肿瘤以限制恶性转化的肿瘤在养分和氧剥夺肿瘤微环境中实现癌细胞的生长和存活（TME）。缺氧与增强的转移和预后不良有关。但是，缺氧的作用 - 肿瘤进展中诱导的自噬尚不清楚。我们已经建立了一种新型的乳房的原位模型自噬在生理和可逆性肿瘤区域被可逆地抑制的癌症。值得注意的是低氧肿瘤区域自噬的丧失会显着增加肺转移而不影响原发性肿瘤生长。此外，与缺氧诱导的自噬的丧失还可以增强肺转移自体抑制的肿瘤。总体而言，我们假设缺氧的丧失 - 诱导的自噬会增加肿瘤应激，以通过与附近的自噬合作促进转移具有高自噬活性的肿瘤亚群体的胜任细胞，驱动转移通过纤连蛋白 - 整合蛋白信号传导和代谢耦合。该假设将以两个特定的测试目的：1）识别和表征在肿瘤亚群中具有增加转移性潜力的肿瘤亚群缺氧引起的自噬或自噬异质性诱导的丧失； 2）调查机制异质性自噬活动通过其中介导肿瘤内细胞通信。这些完成研究将显着增强我们对肿瘤转移自噬的理解，并为适当调节自噬进行癌症治疗。